An overview of the synthetic routes to the best selling drugs containing 6-membered heterocycles

• Marcus Baumann and
• Ian R. Baxendale

Beilstein J. Org. Chem. 2013, 9, 2265–2319, doi:10.3762/bjoc.9.265

Topochemical control of the photodimerization of aromatic compounds by γ-cyclodextrin thioethers in aqueous solution

• Hai Ming Wang and
• Gerhard Wenz

Beilstein J. Org. Chem. 2013, 9, 1858–1866, doi:10.3762/bjoc.9.217

• configuration of the dimeric inclusion complex of the guest. Anti-parallel orientation of acenaphthylene within the CD cavity led to the exclusive formation of the anti photo-dimer in quantitative yield. Parallel orientation of coumarin within the complex of a CD thioether led to the formation of the syn head

• allows for photoreactions even for short-lived excited states. In comparison to other confined and ordered media, most γ-CD thioether complexes offer the advantages of very high quantum yields and excellent stereochemical control. Because the product formation is mainly topochemically controlled

• aqueous solution of the inclusion complex of ACE with γ-CD thioether. Molecular modeling: A previously described procedure was used [25]. The geometries of the orientational isomers of the COU gas-phase dimer were fully optimized without any symmetry restriction at the MP2/6-31G* level of theory by using

Organocatalyzed enantioselective desymmetrization of aziridines and epoxides

• Ping-An Wang

Beilstein J. Org. Chem. 2013, 9, 1677–1695, doi:10.3762/bjoc.9.192

• enantioselectivity of the β-(N-acylamino)aryl thioether (up to 92% ee), with only 1 mol % of chiral guanidine OC-46 as a catalyst. Based on density functional theory (DFT) calculations, a plausible mechanism indicated that the hydrogen-bonding interaction between the chiral guanidine and the carbonyl group in meso-N

True and masked three-coordinate T-shaped platinum(II) intermediates

• Manuel A. Ortuño,
• Salvador Conejero and
• Agustí Lledós

Beilstein J. Org. Chem. 2013, 9, 1352–1382, doi:10.3762/bjoc.9.153

• ) undergoes cyclometalation to form [Pt2(bph)2(μ-SEt2)2] 22 and biphenyl H2bph (Scheme 15) [117]. Intramolecular C–H bond activation seems to be driven by thioether dissociation via 21, a process previously reported for the complex [Pt2(Me)4(μ-SMe2)2] [119]. Marrone et al. computed the cyclometalation process

Space filling of β-cyclodextrin and β-cyclodextrin derivatives by volatile hydrophobic guests

• Sophie Fourmentin,
• Anca Ciobanu,
• David Landy and
• Gerhard Wenz

Beilstein J. Org. Chem. 2013, 9, 1185–1191, doi:10.3762/bjoc.9.133

• localization of the substituents in position 6. This finding is consistent with previous observations of the high binding potentials of CD thioethers for other guests [32][33][39]. The binding constants of the neutral thioether 3 were in most cases higher than the ones of the anionic thioether 4. The high

• cavity 262 Å3 [41], which means that the β-CD cavity within host 4, extended by the thioether substituents, is nearly completely occupied by it. The ability of the program Macromodel (from Schrödinger Inc.) to predict the nonpolar interactions between host 4 and benzene derivatives was finally evaluated

• ]. The host structure was based on a nondistorted β-CD with C7 symmetry, on which primary hydroxyl groups were replaced by thioether arms (with a linear conformation, leading to a tubular extension of the cavity). Guests were constructed manually and submitted to minimization, prior to inclusion

Amyloid-β probes: Review of structure–activity and brain-kinetics relationships

• Todd J. Eckroat,
• Abdelrahman S. Mayhoub and
• Sylvie Garneau-Tsodikova

Beilstein J. Org. Chem. 2013, 9, 1012–1044, doi:10.3762/bjoc.9.116

• monoamine-monoamide bisthiol protected with p-methoxy benzyl (MAMA-PMB, 87) to give 88 (Scheme 7B) [68]. Nitro reduction of 88 followed by thioether deprotection gave MAMA-BTA (89), which was labeled through reaction with the [Re] (used for in vitro studies) or [99mTc] precursors to give the desired 83a,b

• observed that bulky, hydrophobic thioether substituents (such as R4 = SCH2C6H4-p-OMe) were well tolerated at this position. This finding was of particular interest as it provided a possible means of generating new PET ligands via [11C]- or [18F]-labeling through S-alkylation. The [18F]-labeled

Recent progress in the discovery of small molecules for the treatment of amyotrophic lateral sclerosis (ALS)

• Allison S. Limpert,
• Margrith E. Mattmann and
• Nicholas D. P. Cosford

Beilstein J. Org. Chem. 2013, 9, 717–732, doi:10.3762/bjoc.9.82

• (SAR) studies revealed that the thioether and pyridazine moieties were essential molecular components for increasing EAAT2 protein levels [16]. Of the analogues developed, several thiopyridazine derivatives (Figure 4) were found to increase EAAT2 levels greater than six-fold over endogenous levels in

• accumulation, respectively [30]. Metabolic profiling and further chemical modification were performed to increase the stability and potency of ASP derivatives, and this ultimately led to replacement of the thioether with an ether linkage and the identification of a new aryloxanyl pyrazolone (AOP) scaffold

Stereoselective synthesis of tetrasubstituted alkenes via a sequential carbocupration and a new sulfur–lithium exchange

• Andreas Unsinn,
• Cora Dunst and
• Paul Knochel

Beilstein J. Org. Chem. 2012, 8, 2202–2206, doi:10.3762/bjoc.8.248

• thioether such as 1 as an activated alkyne. After a carbocupration of the alkynyl thioether 1 with the organozinc reagent 2 in the presence of CuCN·2LiCl [14], the alkenylcopper species 3 should be obtained. Stereoselective quenching with an electrophile (E1) should afford the tetrasubstituted alkenyl

• thioether 4. Extensive experimentation showed that thioethers 4 do not undergo Ni- or Pd-catalyzed cross couplings leading to products of type 5 (R = Me, Ph) [15][16]. Thus, we designed a new sulfur–lithium exchange (Scheme 1). Sulfur–lithium exchanges proceed only readily with sulfoxides [17][18][19] and

• these reactions are often complicated by radical side reactions [20][21]. This new, direct sulfur–lithium exchange on an alkenyl thioether of type 4 involves the use of a bromobiphenyl R-group, which by treatment with BuLi at low temperatures, undergoes first a fast bromine–lithium exchange leading to

S-Fluorenylmethyl protection of the cysteine side chain upon N^α-Fmoc deprotection

• Johannes W. Wehner and
• Thisbe K. Lindhorst

Beilstein J. Org. Chem. 2012, 8, 2149–2155, doi:10.3762/bjoc.8.242

• led to the fluorenylmethyl-protected thioether 8 in high yield. The suggested mechanism for this reaction comprises the addition of the cysteine thiolate on the exocyclic double bond of dibenzofulvene, which is formed during Fmoc deprotection. The influence of base concentration on this

The chemistry of bisallenes

• Henning Hopf and
• Georgios Markopoulos

Beilstein J. Org. Chem. 2012, 8, 1936–1998, doi:10.3762/bjoc.8.225

Influence of intramolecular hydrogen bonds on the binding potential of methylated β-cyclodextrin derivatives

• Gerhard Wenz

Beilstein J. Org. Chem. 2012, 8, 1890–1895, doi:10.3762/bjoc.8.218

• , such as thioether moieties, is known to furnish host molecules with much higher binding potentials than native β-CD [46][47]. Conclusion The binding potential of β-CD can be improved significantly if hydrophobic substituents are exclusively attached at the primary positions. Intramolecular hydrogen

Molecular solubilization of fullerene C₆₀ in water by γ-cyclodextrin thioethers

• Hai Ming Wang and
• Gerhard Wenz

Beilstein J. Org. Chem. 2012, 8, 1644–1651, doi:10.3762/bjoc.8.188

• of C60 in water reaching concentrations of 15 mg/L. Equilibrium state was approached after seven days without the use of organic cosolvents. The 1:2 stoichiometry of the C60/γ-CD thioether complexes was demonstrated by a parabolic phase-solubility diagram. In contrast, native γ-CD forms nanoparticles

• dissolution of C60 by γ-CD thioethers had been demonstrated, we were interested in how long it takes to reach equilibrium, within experimental error. Therefore a thinly casted film of C60 was incubated with an aqueous solution of γ-CD thioether 7 at 50 °C and stirred according to Kuroda et al. [37]. The slow

• Geckeler for other amino compounds [39]. The phase-solubility diagram of C60 in the presence of γ-CD thioether 3, according to the method established by Higuchi and Connors [40], was obtained by plotting the concentration of the dissolved C60 versus the concentration of the host, as depicted in Figure 4

Intramolecular bridges formed by photoswitchable click amino acids

• Christian Hoppmann,
• Ronald Kühne and
• Michael Beyermann

Beilstein J. Org. Chem. 2012, 8, 884–889, doi:10.3762/bjoc.8.100

• the yield of the intramolecular thiol click reaction increased (Figure 2, data shown for peptide 1). At the highest GSH concentration tested (10 mM), only the intermolecular click product 5 ([M + 2H]2+ = 960.90) was detected as the corresponding sulfoxide of the thioether formed in the crosslinked

Synthesis and antiviral activities of spacer-linked 1-thioglucuronide analogues of glycyrrhizin

• Christian Stanetty,
• Andrea Wolkerstorfer,
• Hassan Amer,
• Andreas Hofinger,
• Ulrich Jordis,
• Dirk Claßen-Houben and
• Paul Kosma

Beilstein J. Org. Chem. 2012, 8, 705–711, doi:10.3762/bjoc.8.79

• spacer elongation [14]. The previously reported 1,2-dehydro-3-thiol derivative 20 was subjected to alkylation with the 2-iodoethyl 1-thioglucuronide compound 6 in the presence of K2CO3 to furnish the thioether-bridged glucuronide triterpene 21 in 60% yield. Deprotection of 21 was performed in two steps

• min, then anisole, TFA, DCM, 0 °C, 3 h, 83% for two steps. Synthesis of 3-thioether-bridged glucuronide derivatives: (a) K2CO3, acetone, 60%; (b) 0.8 M NaOMe, MeOH, 71%; (c) 0.2 M NaOH, MeOH, 95% . Cytotoxic concentration 50% (CC50) of compound-treated uninfected cells and antiviral activities, shown

Synthesis and oxidation of some azole-containing thioethers

• Andrei S. Potapov,
• Nina P. Chernova,
• Vladimir D. Ogorodnikov,
• Tatiana V. Petrenko and
• Andrei I. Khlebnikov

Beilstein J. Org. Chem. 2011, 7, 1526–1532, doi:10.3762/bjoc.7.179

• characterized. Oxidation of the pyrazole-containing thioether by hydrogen peroxide proceeds selectively to provide a sulfoxide or sulfone, depending on the amount of oxidant used. Oxidation of the benzotriazole derivative by hydrogen peroxide is not selective, and sulfoxide and sulfone form concurrently

• . Selenium dioxide-catalyzed oxidation of benzotriazole thioether by H2O2, however, proceeds selectively and yields sulfoxide only. Keywords: azole; oxidation; sulfone; sulfoxide; thioether; Introduction Compounds comprising two pyrazole moieties linked by an aliphatic spacer act as bidentate chelating

• dismutase-like activity of copper(II) complexes with bis(pyrazole) ligands [5][6]. Copper(II) complexes with azole-derived thioether ligands were proposed as models for type I copper proteins [7]. The sulfur atom in a thioether spacer gives an additional possibility for modification of the ligand structure

Amines as key building blocks in Pd-assisted multicomponent processes

• Didier Bouyssi,
• Nuno Monteiro and
• Geneviève Balme

Beilstein J. Org. Chem. 2011, 7, 1387–1406, doi:10.3762/bjoc.7.163

• , thioether and ester groups, although enolizable alkylimines were not suitable under these conditions (Scheme 1). Replacement of the acid chloride with a chloroformate under 1 atmosphere of carbon monoxide as a fourth component led to ketocarbamates 3 in a single operation through a carbonylative coupling [3

Amine-linked diglycosides: Synthesis facilitated by the enhanced reactivity of allylic electrophiles, and glycosidase inhibition assays

• Ian Cumpstey,
• Jens Frigell,
• Elias Pershagen,
• Tashfeen Akhtar,
• Elena Moreno-Clavijo,
• Inmaculada Robina,
• Dominic S. Alonzi and
• Terry D. Butters

Beilstein J. Org. Chem. 2011, 7, 1115–1123, doi:10.3762/bjoc.7.128

• diglycoses (or neodisaccharides), are linked by ether, amine, thioether, selenoether, etc., bridges, and so are presumably more stable to hydrolysis by acid or glycosidases than (glycosidic) disaccharides. Diglycoses have many features in common with disaccharides, with a similar general appearance, size

• disaccharide mimicry. Last year, we reported that neutral ether- and thioether-linked diglycose derivatives can interact with lectins with affinities similar to those of strongly binding disaccharide ligands [4]. In the related carbasugar series, Ogawa et al. have shown that pseudodisaccharides with a bridging

• nitrogen atom bind more strongly to glycosidases than do the corresponding ether or thioether derivatives [5]. It follows that amine-linked diglycose derivatives may act as glycosidase inhibitors. We set about the synthesis of some compounds of this type to test this hypothesis. In our initial

Asymmetric synthesis of tertiary thiols and thioethers

• Jonathan Clayden and
• Paul MacLellan

Beilstein J. Org. Chem. 2011, 7, 582–595, doi:10.3762/bjoc.7.68

• products 16 with complete inversion of configuration [16][17]. Acid catalysed cleavage of a thioether or thioacetate yields tert-thiols 17 in good yield. 1.1.2 Epoxide ring opening SN2 displacements from quaternary electrophiles require specific structural features to avoid competing racemisation

• of the leaving group with a 1,4-benzoquinone derivative, DBBQ (35) being most effective (Scheme 12). Addition of a thiol nucleophile to adduct 32 results in SN2 inversion and isolation of the enantiomerically pure (94:6–99:1 er) tertiary thioether 33 and by-product 34. Highest yields were obtained

• with BtzSH (36) and BoxSH (37). The reaction proceeds well with many hindered substrates incorporating aromatic, alkyl and ester substituents with excellent stereospecificity. Enantiomerically pure thiols can also be made from the product: Aromatic thioether 38 is reduced with lithium aluminium hydride

Kinetic evaluation of the solvolysis of isobutyl chloro- and chlorothioformate esters

• Malcolm J. D’Souza,
• Matthew J. McAneny,
• Dennis N. Kevill,
• Jin Burm Kyong and
• Song Hee Choi

Beilstein J. Org. Chem. 2011, 7, 543–552, doi:10.3762/bjoc.7.62

• enzyme elastase [66]. In Figure 1, the 3-D images of isobutyl chloroformate (1') and isobutyl chlorothioformate (2') are presented. In these figures, it is clear that the isopropyl group is pushed out of the plane due the presence of a carbon atom next to the ether or thioether atom in 1' and 2'. This

• 25.0 °C. In pure methanol and ethanol a dominant association–dissociation (addition–elimination) mechanism, with rate-limiting addition, is believed to be effective in all four substrates. This rate order indicates that the inductive ability of the alkyl thioether group is almost independent of the

• resonance-stabilized carbocation intermediate is more efficient for isopropyl chlorothioformate (5) when compared to 2, as the presence of the additional carbon pushes the isopropyl group out of the plane of the thioether atom in 2' (Figure 1). This opinion is supported by an increase seen in the l/m ratio

Photoinduced electron-transfer chemistry of the bielectrophoric N-phthaloyl derivatives of the amino acids tyrosine, histidine and tryptophan

• Axel G. Griesbeck,
• Jörg Neudörfl and
• Alan de Kiff

Beilstein J. Org. Chem. 2011, 7, 518–524, doi:10.3762/bjoc.7.60

•  1). For example, the glutamic acid derivative 3 resulted in the formation of a diastereoisomeric mixture of benzopyrrolizidinones 4 [6]. For a specific system, N-phthaloyl methionine (5), we have detected bielectrophoric behavior in that the electron transfer from the thioether group competes

An overview of the key routes to the best selling 5-membered ring heterocyclic pharmaceuticals

• Marcus Baumann,
• Ian R. Baxendale,
• Steven V. Ley and
• Nikzad Nikbin

Beilstein J. Org. Chem. 2011, 7, 442–495, doi:10.3762/bjoc.7.57

• esomeprazole the subsequent steps involve an S-alkylation as well as an asymmetric oxidation of the newly formed thioether [59][60]. Additional structural diversity in the aniline component can be introduced by protection, nitration, deprotection and reduction of the starting amine compound 201. Scheme 40 for

Aromatic and heterocyclic perfluoroalkyl sulfides. Methods of preparation

• Vladimir N. Boiko

Beilstein J. Org. Chem. 2010, 6, 880–921, doi:10.3762/bjoc.6.88

• carbanion (RF−) in turn reacted with the sulfenyl iodide to generate a thioether. However, RFCH3 and RFH, are also obtained as by-products, which may be a result of homolytic decomposition of the perfluoroalkyl iodides at high temperature [130][131]. Similarly, reactions of RFI with sodium thiophenoxide

• , CF3I is a poorer electrophile than C3F7I - even under biphasic conditions. 4.1.4. Interaction of thiols with perfluoroalkyl bromides Although brominated perfluoroalkanes are cheaper and more readily available than the corresponding iodides, they react more slowly in thioether forming reactions. In

Kinetic studies and predictions on the hydrolysis and aminolysis of esters of 2-S-phosphorylacetates

• Milena Trmčić and
• David R. W. Hodgson

Beilstein J. Org. Chem. 2010, 6, 732–741, doi:10.3762/bjoc.6.87

• k0 = 1.8 × 10−3 min−1 and 1.1 × 10−3 min−1, respectively with other 2-substituted acetates may provide insight at this point. Holmquist and Bruice have studied the hydrolysis kinetics of 2-nitrophenyl 2-(ethylthio)acetate at 30 °C [10], which is a thioether as opposed to the S-bridging-thiophosphates

Molecular recognition of organic ammonium ions in solution using synthetic receptors

• Andreas Späth and
• Burkhard König

Beilstein J. Org. Chem. 2010, 6, No. 32, doi:10.3762/bjoc.6.32

Synthesis of methylenebisamides using CC- or DCMT- activated DMSO

• Qiang Wang,
• Lili Sun,
• Yu Jiang and
• Chunbao Li

Beilstein J. Org. Chem. 2008, 4, No. 51, doi:10.3762/bjoc.4.51

• the attack of the amide on the sulfonium ion 1. When the reaction is carried out in toluene, intermediate 1 decomposes into intermediate 2. Thioether 3 is formed by the addition of the amide to intermediate 2. N-(Methylthiomethyl)octanamide (40% yield) was isolated when octanamide was treated with

• DCMT in DMSO. Similarly, N-(1-(methylthio)-2-oxo-2-phenylethyl)benzamide (30% yield) was isolated when benzamide reacted with DCMT and 2-(methylsulfinyl)-1-phenylethanone. Thioether 3 is a good nucleophile and capable to substitute the chloride of CC or DCMT to generate sulfonium salt 5. The amide

• substitutes the thioether of 5 to form methylenebisamides 6. Conclusion In conclusion, we have developed a simple and efficient procedure to produce methylenebisamides in good yield via the reaction of amides with CC- or DCMT-activated DMSO. The procedure reported herein is operationally simple, and requires